We propose to lay essential groundwork for a unique, potentially transformational, model system-agnostic, Synchrotron MicroCT Imaging Resource for Biology (SMIRB). Tissue phenotypes provide insights that are central to our understanding of gene function and environmental variables such as chemical exposures. Phenotypes can occur anywhere in an organism and during any time in the organism's life. To capture the full breadth of phenotypic tissue effects, organisms must ideally be evaluated across the full life span and in every cell type and organ system. We show that synchrotron microCT has the power to image mm length scale organisms at cellular resolution to produce high-contrast, 3D reconstructions of every cell in the whole organism. With these data, phenotypes occurring at different scales (system, tissue, or cell) can be evaluated simultaneously slice-by-slice or in 3D context to reveal valuable spatial relations. Accessing this tool is currently a highly involved process that is not practical for routine biology. On the basis of our data, attendees of an NHGRI-sponsored zebrafish phenome meeting, investigators meetings, two Zebrafish Models of Human Disease meetings, biologists working at Karlsruhe Institute of Technology, and two toxicology meetings have agreed that methods for high-throughput synchrotron-based microCT should be developed for phenotyping model system samples. Investigators working in NIH-sponsored small model systems including Drosophila, C. elegans, and Daphnia, have become interested in phenotyping their organisms. This work will allow us to establish the user base and technical foundation for a new beamline dedicated to biology, which has been approved by the Scientific Advisory Council and the Director of the Advanced Photon Source at Argonne National Laboratory for further pursuit. Accessibility to the broader biological community requires customization of the imaging process for biological samples. An interdisciplinary team will bring key steps in synchrotron- based microCT imaging to a stage that computer scientists can enhance to achieve speeds practical for phenome projects to be completed within reasonable periods of time. We will design and implement throughput-oriented enhancements including design of sample formats for reproducible and robotic sample loading, optimization of optical components, and streamlining of image processing. We have set milestones, and will work iteratively with investigators involved in potential zebrafish, Drosophila, elegans, and Daphnia phenome projects. Broader applications of the developed tools have large potential translational impacts. Given the uniquely pan-cellular nature of the 3D images, this work will not only facilitate research with any biological model system, but also any organ system, including nervous, digestive, endocrine, reproductive, excretory, and integumentary systems. The ability to capture the effects in any part of the organism resulting from gene or environmental variables means that the research is likely to address the assigned mission of NIH, NIEHS, EPA, FDA, and DOD.

Public Health Relevance

The purpose of phenomics is to probe the biological functions affected in genetically or environmentally modified organisms through detailed phenotypic analysis. We are laying the groundwork for a new, state-of-the-art, high-throughput synchrotron microCT imaging resource for biology that will allow the creation of 3D reconstructions of opaque tissues including whole organisms such as zebrafish, Drosophila and mammalian tissue samples. This method uniquely creates 3D images of all cell types from all organ systems (pan-cellular imaging) at cell resolution, which has the potential to profoundly accelerate understanding of human gene function, drug development and assessment of human and environmental exposures.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZRG1)
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Contreras, Miguel A
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Pennsylvania State University
Schools of Medicine
United States
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Copper, Jean E; Budgeon, Lynn R; Foutz, Christina A et al. (2018) Comparative analysis of fixation and embedding techniques for optimized histological preparation of zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 208:38-46
Cheng, Keith C; Xin, Xuying; Clark, Darin P et al. (2011) Whole-animal imaging, gene function, and the Zebrafish Phenome Project. Curr Opin Genet Dev 21:620-9